Letter pubs.acs.org/OrgLett
Diels−Alder Reactions of Furans with Itaconic Anhydride: Overcoming Unfavorable Thermodynamics Ashok D. Pehere, Shu Xu, Severin K. Thompson, Marc A. Hillmyer, and Thomas R. Hoye* Department of Chemistry, University of Minnesota, 207 Pleasant Street, SE, Minneapolis, Minnesota 55455, United States S Supporting Information *
ABSTRACT: Unfavorable thermodynamics often render furans reluctant to engage in high-yielding Diels−Alder (DA) cycloaddition reactions. Here, we report the highly efficient conversion of the biosourced reactants itaconic anhydride (IA) and furfuryl alcohol (FA) to a single DA adduct. The free energy advantages provided by anhydride ring opening and crystal lattice energy of the product overcome the loss of aromaticity of the furanoid diene. Detailed 1H NMR studies provided valuable insights about relevant kinetic and thermodynamic features.
I
taconic acid1 and furfural2 are two chemicals abundantly available from biomass. The first arises by the classical citric acid (or tricarboxylic or Krebs3) cycle and the second by acidcatalyzed dehydration of 5-carbon sugars prevalent in, for example, corncobs (see Volume 1 of Organic Syntheses4). For a century, it has been known that each itaconic anhydride (1, IA) and furfuryl alcohol (2, FA) is readily available by simple conversions (dehydration5 and reduction,6 respectively) of these readily available precursors. The ability of IA to function as a dienophile in Diels−Alder (DA) cycloaddition reactions was described even in the first publication by Diels and Alder.7 The use of furan as a diene was reported 1 year later in their second paper on the subject of “hydroaromatic synthesis”.8 Remarkably, we can find no reports of IA (1) or itaconic acid (or its esters) ever having been reacted with any furan derivative in the intervening >85 years. This is in spite of the fact that DA adducts of furans with many other types of dienophiles have been appropriated as strategically valuable and enabling intermediates in numerous syntheses of complex molecules.9 With an eye toward the preparation of novel reactive monomers from furans for use in sustainable polymer synthesis,10 we have studied the reactions of IA (1) with various furans and report our findings here. A hallmark of furans as participants in DA cycloadditions is the often unfavorable enthalpic change upon product formation. This frequently results in only low equilibrium conversion to the [4 + 2] adduct because of loss of heteroaromaticity in the diene and ring strain in the 7-oxanorbornene product.11 This is all the more true for 1,1disubstituted dienophiles analogous to 1 (e.g., methacrolein,12a methacrylates,12a−c and methacrylonitrile12d), where the equilibrium concentration of product ranges from 7 to 36% even in the presence of 20-fold excess of furan, at low temperature, and/or under high pressure. We first describe reactions between IA (1) and a variety of simple furans, starting with furan 3. In one experiment, IA was dissolved in 20 equiv of furan and held at ambient temperature. Aliquots were periodically withdrawn and dissolved in CDCl3 to monitor reaction progress. It was important in this kind of © 2016 American Chemical Society
analysis that the spectral data be recorded soon after sample preparation because the retro-Diels−Alder reaction was also operative at room temperature, and dilution (here, from neat to NMR sample concentration) shifts the equilibrium composition of this bimolecular-to-unimolecular process toward the starting pair of reactants (here, 1 + 3). Two diastereomeric products, 4endo and 4-exo, are produced (Figure 1a and Table 1, entry 1).
Figure 1. (a) Rate and final equilibrium resting state for the DA reaction between IA (1) and furan 3. (b) Conversion of 4-endo to 5 via 4-endoh2 and 3D structure of 5 from a single-crystal X-ray analysis. [Cambridge Crystallographic Data Centre (CCDC) deposition #1481187]. aThis is the half-time for reaching the final equilibrium mixture (the ratio for 1/4-exo/4-endo was 73:13:14).
Even at early time points, they formed at nearly identical rates. After 40 h, the system had essentially reached its equilibrium state, which comprises a ratio of 73% of the initial IA (1) and 27% of the sum of the two DA adducts. At equilibrium, there was a very slight predominance of 4-endo over the amount of 4-exo. These diastereomeric DA adducts were sufficiently stable to be isolable by rapid chromatographic separation on silica gel, even though some retro-DA reaction was occurring as the solutions were being manipulated. Isolated solid-state samples of each Received: March 31, 2016 Published: May 23, 2016 2584
DOI: 10.1021/acs.orglett.6b00929 Org. Lett. 2016, 18, 2584−2587
Letter
Organic Letters
constitutional isomers. Again, we used an excess of the furan component as the solvent in this ambient temperature experiment and monitored the reaction progress over time. We observed (i) that the proximal isomers are formed more quickly than the distal, a reasonable event given the electronic polarization imparted by the donor methyl group in 8; (ii) that the distal isomers eventually predominated over the proximal, again reasonable, now on the basis of minimization of steric compression; and (iii) that the equilibrium amounts of the four products (Table 1, entry 3) are in line with the observed equilibrium ratios of DA adducts 4 and 7. Finally, the overall extent of conversion was intermediate between that of furan and the 2,5-dimethylated derivative 6. 2-Acetoxymethylfuran (10) was another diene substrate that proved informative (Table 1, entry 4). At equilibrium, the four IA DA adducts 11 were formed, again to an extent intermediate between that of 4 versus 7. This was observed to be the slowest of all reactions we studied, consistent with the acetoxymethyl substituent having a weakly electron-withdrawing character. As was the case for 9, at equilibrium, the distal isomers predominated. The assignments of structure to the distal versus proximal substitution patterns among the isomers of 9 and 11 were based on the difference in coupling patterns of the resonances for the bridgehead protons (at C4) in each (see SI). HMQC and HMBC NMR analyses also were consistent with the assignments. We then turned to the reaction between the bioderived FA (2) and IA (1). Initially, we monitored the behavior of an equimolar mixture of this diene/dienophile pair in CDCl3 solution (∼1.5 M). After being held at 55 °C for 10 min, a few percent of total conversion to a mixture of four DA adducts was seen, which is well in line with the behavior (rate and ratio) observed for the reaction between the acetate 10 and 1. By analogy then, we presumed these four compounds to be a mixture of the four isomeric anhydrides 12 (Figure 2a). When this reaction solution was examined after 7 days, a new, fifth component was seen to emerge at about 15% relative to the unconsumed IA (1). The appearance of (i) a broad downfield resonance and (ii) a pair of downfield doublets (δ 4.62 and 4.83, Jab = 10.8 Hz) in this new, dominant compound suggested that a carboxylic acid lactone had formed; it is reasonable to anticipate a conversion of one of 12prox-exo or 12-prox-endo to a ring-opened lactone acid by one of the four pathways implied by arrows “a” or “b” in 12-prox-exo or “a′” or “b′” in 12-prox-endo (Figure 2a). The favorable free energy change associated with anhydride opening provides a driving force for DA adduct formation. The significant breakthrough was achieved when an equimolar mixture of 1 and 2 was allowed to react in the bulk. A suspension of solid 1 (95% grade) in liquid 2 (98% grade) at ambient temperature changed over time in consistency. After about 3.5 h, the initial heterogeneous slurry could no longer be magnetically stirred; we could identify in the NMR spectrum of an aliquot the presence of all four isomeric anhydrides 12 (Figure 3), albeit to the total extent of only ca. 5%, along with a significant amount of the same fifth component mentioned above. After 10 h, the composition of the bulk mixture was that of a paste, and after 18 h, it had turned to a solid mass. This material now comprised largely a single component, having the same spectral properties as those of the new, fifth component that had appeared after 7 days in the homogeneous CDCl3 solution experiment described above. The 13C NMR spectrum of this compound showed a carbonyl resonance at δ 177.8 ppm, suggestive that it contained a five-membered butyrolactone ring.13 X-ray diffraction showed
Table 1. Reactions of Itaconic Anhydride (1) with Furans 3, 6, 8, and 10 (20 equiv) at Ambient Temperature
isomer were considerably more stable. Upon dissolution in CDCl3 or C6D6, each isomer began to slowly revert to 1 and 3 (ca. 50% conversion after 6 h), consistent with the rate of their formation and final equilibrium ratios. Our assignment of the diastereomeric relationship within each of the 4-exo and 4-endo was initially based on detailed analyses of NMR data [see Supporting Information (SI)]. This was subsequently confirmed by an X-ray structure of the diacid 5 (Figure 1b) obtained by catalytic hydrogenation of 4-endo to the derivative 4-endo-h2, which was then hydrolyzed to the crystalline diacid 5. Diagnostic features in the 1H NMR spectral data of each diastereomer of 4 were then useful in assessing the relative configuration of the DA adducts prepared from additional furan derivatives (cf. 4, 7, 9, and 11 in Table 1); details are provided in the SI. 2,5-Dimethylfuran (6) was the next diene studied, again in an experiment where it was used as the reaction solvent and in ca. 20-fold excess over IA (1). The results are summarized in Table 1 (entry 2). The reaction of 6 with 1 was notably faster than that of furan (t1/2 ∼ 15 min vs ∼8 h at 23 °C); apparently, the greater electron density in diene 6 is a more important factor than the increase in its steric bulk. However, the reaction proceeded to a considerably lower equilibrium conversion (ca. 5%) of the sum of DA adducts 7-endo and 7-exo, which reflects the greater steric compression between the substituents on the spirocyclic carbon and the adjacent (proximal) bridgehead methyl group present in adducts 7 vis-à-vis adducts 4. At an intermediate time point (10 min, ca. 3% conversion), formation of the major isomer had outpaced that of the minor to the extent of ca. 2:1, a ratio that remained essentially constant thereafter. We next examined the reaction of IA with 2-methylfuran (8), a desymmetrized diene that could give rise to four isomeric, NMRdistinguishable DA adducts. These are a pair of endo and exo diastereomers for each of a distal (9-dist-endo and 9-dist-exo) versus a proximal (9-prox-endo and 9-prox-exo) pair of 2585
DOI: 10.1021/acs.orglett.6b00929 Org. Lett. 2016, 18, 2584−2587
Letter
Organic Letters
Figure 2. (a) Reaction manifold showing the equilibration among 1 + 2, four isomeric anhydrides 12, lactone acids 13 and 14, and monofurfuryl itaconates 15. (b) DFT [M06-2X/6-31+G(d,p) (SMD/CHCl3); see SI for details] free energies (kcal·mol−1) of the four isomeric lactone esters from ring opening of 12-prox-endo and 12-prox-exo and the (more stable) monofurfuryl itaconate esters 15a and 15b. (For X-ray structure details see CCDC deposition #1481188).
Figure 3. 1H NMR spectrum in acetone-d6 of an aliquot of the bulk reaction mixture from 1:1 IA (1) and FA (2). (a) Resonances from the major product 14 are assigned. (b) Vertical scale increased 5×; the principal minor components are denoted; integration of all components indicates a 94% yield of 14 (see SI for full-page version of this graphic).
Crystal lattice energies have been exploited for additional purposes in the arena of furan DA chemistry.14 A sample removed from the bulk mixture of 1 and 2 after just 30 min was immediately chromatographed on silica gel. The structures of three constituents, each obtained in
